Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1.
Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1.
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人琥珀酰辅酶 A：戊二酸辅酶 A 转移酶（1 型戊二酸尿症的遗传修饰剂）的表征、结构和抑制。
DOI：
10.1101/2024.02.07.578422
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Houten,SanderM
中科院分区：
文献类型：
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作者：
Khamrui,Susmita;Dodatko,Tetyana;Wu,Ruoxi;Leandro,João;Sabovic,Amanda;Violante,Sara;Cross,JustinR;Marsan,Eric;Kumar,Kunal;DeVita,RobertJ;Lazarus,MichaelB;Houten,SanderM
戊二酸尿1型（GA1）是一种严重的先天性代谢错误，没有药物治疗。一种新的治疗策略是将有毒的生化中间体转移到毒性较小或无毒的代谢物上。在这里，我们报告了一个新的靶点，SUGCT，我们假设它通过降低戊二酰辅酶a来抑制GA1代谢表型。我们报道了SUGCT的结构，这是III型辅酶a转移酶的第一个真核结构，开发了高通量酶测定和基于细胞的测定，并鉴定了缬沙坦和氯沙坦羧酸作为酶的抑制剂，验证了筛选方法。这些结果可能为未来开发治疗GA1的新药物干预奠定基础。
Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or non-toxic metabolites. Here, we report a novel target, SUGCT, which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA. We report the structure of SUGCT, the first eukaryotic structure of a type III CoA transferase, develop a high-throughput enzyme assay and a cell-based assay, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme validating the screening approach. These results may form the basis for future development of new pharmacological intervention to treat GA1.